Patients homozygous for familial hypercholesterolemia (FH) manifest profound hypercholesterolemia, cutaneous cholesterol deposits termed xanthomas, and cholesterol deposition in a variety of tissues including the eye, tendons, and inside the arterial vessels. These patients experience accelerated atherosclerosis and can manifest symptomatic cardiovascular disease from the ages of 2-30 years, and many die before the age of 20. The cause for the 10 fold increase in total and low density lipoprotein (LDL) cholesterol concentrations is a defect in the ability of the body to extract the cholesterol-rich LDL particles from the circulation via the LDL receptor pathway. More than 150 mutations in the LDL receptor gene can lead to the loss of the expression of functional LDL receptors on the surface of liver cells. We have previously demonstrated that the degree of LDL receptor dysfunction on cultured skin fibroblasts from these patients highly correlates with the concentrations of LDL cholesterol present in their circulation. We have applied a variety of therapies to reduce the LDL cholesterol concentrations in these patients including diet, combination hypolipidemic drug therapy, portacaval shunting of the liver, plasma exchange, LDL apheresis, liver transplantation, and most recently, adenoviral gene therapy. The degree of coronary artery atherosclerosis and the response to lipid-lowering intervention is variable among patients identified as having this condition. For the past 6 years we have prospectively evaluated the rate of progression of atherosclerosis by both invasive and noninvasive techniques in these patients. We have demonstrated that assessment of the extent and severity of both cholesterol deposition into tissues and in atherosclerosis using computerized axial tomography. This noninvasive test led to a new concept in atherosclerotic cardiovascular disease risk assessment, the cholesterol-years risk score. These findings in this inborn error in lipoprotein metabolism may have theoretic and practical implications for individuals with more common forms of atherosclerosis.